Malaria has undergone a striking expansion in recent years, both its range and mortality, due in part to the appearance of multiple drug resistant strains of Plasmodium falciparum. The re-emergence of malaria in regions where it had been eradicated of special concern to health official. Despite the magnitude of the problem, the mechanism(s) of parasite resistance to the majority of anti-malarial drugs are not clearly understood. The experiments outlined in this proposal will examine the molecular basis of drug resistance using the rodent malaria species Plasmodium berghei. Emphasis will be placed on homologous of mdr genes have been implicated in treatment failures of mammalian neoplastic cells. The specific aims are: (1) to establish the role of the multi-drug resistance (pbmdr1) gene in P. berghei through gene disruption and localization of the gene product; and (2) to identify novel genes potentially involved in malaria drug resistance, including the genes encoding the role of the rodent malaria P. berghei mdr1 gene, the reading frame will be disrupted by transfection and the resulting pattern of drug resistance will be assayed. Furthermore, the expression and intracellular localization of the protein will be investigated. Other candidate genes (mrp and ggcs) will be identified using the polymerase chain reaction and degenerate primers based on highly conserved sequences. The potential association of these gene fragments with drug resistance will be investigated in a collection of drug sensitive and multi-drug resistant lines of P. berghei.